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Abnormal Sialylation Promotes Chemotherapy Resistance in Bladder Cancer via the PI3K-AKT-mTOR Signaling Pathway
by
Junlong Zhu
, 
Aimin Wang
,
Hang Tong
,
Yan Sun
,
Tinghao Li
,
Linfeng Wu
,
Xiaoyu Zhang
,
Zijia Qin
and
Weiyang He
* Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
*
Author to whom correspondence should be addressed.
Cancers 2026, 18(11), 1713; https://doi.org/10.3390/cancers18111713 (registering DOI)
Submission received: 2 April 2026
/
Revised: 14 May 2026
/
Accepted: 19 May 2026
/
Published: 24 May 2026
(This article belongs to the Special Issue Cancer-Associated Fibroblasts and Translational Biomarkers in Tumor Progression, Metastasis and Therapy Response)
Simple Summary
Bladder cancer is a common cancer of the urinary system, but patients often respond differently to treatment. Although gemcitabine plus cisplatin chemotherapy remains an important treatment option, some patients still experience recurrence, progression, or drug resistance. These differences may be influenced by changes within tumor cells and by the surrounding tumor microenvironment. This study focused on sialylation-related molecules, which are involved in sugar modifications on the cell surface, and explored their relationships with patient prognosis, tumor microenvironment features, and chemotherapy resistance in bladder cancer. The findings may help researchers better understand how bladder cancer progression and drug resistance develop. They may also provide useful clues for future risk assessment, prediction of treatment response, and development of new therapeutic strategies.
Abstract
Background: Aberrant glycosylation is closely associated with tumor progression, changes in the tumor microenvironment, and chemoresistance. This study aimed to identify prognostic sialylation-related genes in bladder cancer and define the role of ST3GAL6 in gemcitabine–cisplatin resistance. Methods: Molecular subtype analysis, prognostic analysis, and risk model construction were performed for sialylation-related genes using transcriptomic data and clinical information from the TCGA database. GC-resistant bladder cancer cell models were established for transcriptomic sequencing and untargeted metabolomic analysis. Cell proliferation and drug sensitivity assays were performed to evaluate the function of ST3GAL6. The regulatory relationship between IGF2BP3, ST3GAL6, and the PI3K pathway was further assessed by combining database analysis with molecular experiments. Results: Sialylation-related molecular patterns were associated with patient prognosis and tumor microenvironment features, particularly fibroblast-related characteristics, in bladder cancer. The key model gene ST3GAL6 was upregulated in bladder cancer tissues and was closely associated with prognosis. In GC-resistant bladder cancer cells, ST3GAL6 expression was significantly increased and accompanied by enhanced sialylation activity. ST3GAL6 promoted bladder cancer cell proliferation and reduced sensitivity to cisplatin and gemcitabine, at least in part through the PI3K-AKT-mTOR pathway. IGF2BP3 was also upregulated in resistant cells, is positively correlated with ST3GAL6, and may help maintain ST3GAL6’s expression by stabilizing its mRNA. Conclusions: Our findings suggest that aberrant sialylation is involved in bladder cancer progression and GC resistance. The IGF2BP3-ST3GAL6-PI3K/AKT/mTOR signaling axis may contribute to this process and may serve as a potential biomarker and therapeutic target in bladder cancer.
